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Update on Preventing Pneumococcal Disease in Adults

In the article by File et al, appearing in Infectious Diseases in Clinical Practice, Vol. 20, No. 1, pp. 3–9, entitled “Update on Preventing Pneumococcal Disease in Adults”, the following commercial support information was inadvertently omitted from the submission: “This activity is supported by an unrestricted educational grant from Merck & Co., Inc.”

This publication is based on an expert roundtable discussion held in October 2011 titled “Preventing Adult Pneumococcal Disease: Know Your Options.”

Abstract

Abstract: Invasive pneumococcal disease (IPD) is responsible for substantial clinical and economic burden in adults. Despite the safety and effectiveness of pneumococcal vaccines in protecting against these serious infections, immunization of eligible adults remains largely underused. The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices has recently expanded the use of the pneumococcal vaccine to include adults with asthma and all cigarette smokers, in addition to persons previously designated as at-risk. Improving adult pneumococcal immunization rates will require efforts from a broad range of healthcare providers. Clinicians should take a proactive approach in recommending the vaccine to eligible adults and should implement strategies that remove barriers to immunization efforts.

EDUCATIONAL OBJECTIVE

Describe the healthcare burden of pneumococcal disease among adults; evaluate the benefits and limitations of pneumococcal vaccines for use in specific patient populations; identify adults at risk for pneumococcal disease and patients who will benefit from vaccination; and understand when to vaccinate adult patients in accordance with current clinical practice recommendations in an effort to improve pneumococcal vaccination rates.

PARTICIPATION IN THE LEARNING PROCESS

Credit is based upon the approximate time it should take to read this publication and complete the assessment and evaluation. A minimum assessment score of 80% is required. Publication date is January 1, 2012. Requests for credit or contact hours must be postmarked no later than July 1, 2012, after which this material is no longer certified for credit.

DISCLOSURE

NFID must ensure balance, independence, objectivity, and scientific rigor in its educational activities. All individuals with control over content are required to disclose any relevant financial interest or other relationship with manufacturer(s) of any product or service discussed in an educational presentation and/or with the commercial supporters of this activity. Disclosure information is reviewed in advance to manage and resolve any conflict of interest, real or apparent, that may affect the balance and scientific integrity of an educational activity.

Thomas M. File, Jr, MD (faculty), served as an advisor or consultant for Astellas/Theravance, Cerexa/Forest, DaiichiSankyo, GlaxoSmithKline, Merck, Nabriva, Pfizer Inc, and Tetraphase and received grants for clinical research from Cempra, Pfizer Inc, and The Medicines Company.

Susan J. Rehm, MD (senior editor), served as an advisor or consultant for Merck and Pfizer Inc and served as a speaker for Genentech.

Michael D. Hogue, PharmD (faculty), served as an advisor or consultant for Pfizer Inc and served as a speaker for Merck.

Kristin L. Nichol, MD, MPH, MBA (faculty), served as an advisor or consultant for GlaxoSmithKline, MedImmune, Merck, and Novartis.

William Schaffner, MD (faculty), served as an advisor or consultant for Dynavax, GlaxoSmithKline, Merck, Novartis, Pfizer Inc, and Sanofi Pasteur.

No fee is required. Please allow 4 to 6 weeks for processing. Inquiries may be directed to 301-656-0003 x16 or e-mail to info@nfid.org.

Pneumococcal disease includes conditions such as respiratory tract infections (community-acquired pneumonia, sinusitis, and acute exacerbations of chronic bronchitis) and more serious invasive infections such as bacteremia (often with pneumonia as the source) and meningitis.

According to the Centers for Disease Control and Prevention (CDC), in the United States in 2009, an estimated 43,500 cases of invasive pneumococcal disease (IPD) resulted in approximately 5000 deaths.1 In addition to the clinical burden, the economic costs associated with pneumococcal disease are substantial. The total costs of pneumococcal disease (direct medical costs, sequelae, work loss costs, and future productivity loss) were estimated to be $7.72 billion annually.2

POPULATIONS AT RISK OF IPD

Epidemiological studies have demonstrated that certain adult populations are at an increased risk of IPD. Older adults are particularly vulnerable—a CDC study revealed that 38% of IPD (bacteremia and meningitis) occurred in persons 65 years and older, whereas 20% of IPD cases occurred in adults 50 to 65 years.2 Immunocompromised populations are also at greater risk of IPD and its associated morbidity and mortality. A study by Feikin et al3 revealed several risk factors for death due to IPD in the immunocompromised population (Table 1). Adults infected with the human immunodeficiency virus (HIV) are at a much higher risk of IPD. A review of 13,812 cases of IPD (1998–2007) from 7 Active Bacterial Core surveillance areas found that 23% of cases occurred among HIV-infected adults.4

Cigarette smoking has long been recognized as a risk factor for IPD. Earlier studies have shown that smokers account for nearly half of otherwise healthy adults with IPD.5 In a population-based case-control study, 228 cases (18- to 64-year-olds who had IPD) were compared with 301 controls.6 Cigarette smokers comprised 58% of cases and 24% of the controls. IPD was strongly associated with cigarette smoking (odds ratio [OR], 4.1; 95% confidence interval [CI], 2.4–7.3) as well as passive smoking among nonsmokers (OR, 2.5; 95% CI, 1.2–5.1). There was a strong association between the risk of IPD and the number of cigarettes smoked per day, pack-years of smoking, and the time since quitting. The risk for pneumococcal disease decreased approximately 14% per year since quitting smoking. Former smokers were found to be at increased risk of IPD for more than 10 years after quitting.

Fortunately, pneumococcal vaccines offer an effective and safe approach to prevent IPD in the at-risk population.

PNEUMOCOCCAL VACCINES AND THEIR IMPACT

Of the approximately 90 known serotypes of pneumococci, each distinguished by the antigenicity of its capsular polysaccharides, only a minority is responsible for most IPD cases in children and adults. Currently, 2 types of pneumococcal vaccines are available for protection against IPD—the pneumococcal polysaccharide vaccine (PPSV) and the pneumococcal conjugate vaccine (PCV) (Table 2).

Pneumococcal Polysaccharide Vaccine

The PPSV contains multiple purified polysaccharides in a single dose. The first PPSV, a 14-valent PPSV (or PPSV14) for use in adults in 1977, was replaced by the 23-valent PPSV (or PPSV23) in 1983.

The efficacy of PPSV was demonstrated in a study by Butler et al.7 The study used an indirect cohort analysis to compare the proportion of pneumococcal infections caused by serotypes included in PPSV14 and PPSV23 among the vaccinated and unvaccinated persons older than 5 years. Using data from 2837 persons who had pneumococci isolated from their blood or cerebrospinal fluid, vaccination was associated with a 57% efficacy in preventing infection, although the rate increased to 75% in immunocompetent adults 65 years and older (Table 3). The efficacy was lower among adults with certain immunosuppressive conditions, such as Sickle cell anemia, Hodgkin disease, chronic renal failure, leukemia, and multiple myeloma. However, the small number of patients within these subgroups raises questions regarding the significance of these results.

More recently, a meta-analysis of all randomized controlled trials (RCTs) and non-RCTs compared PPSV with placebo, control vaccines, or no intervention.8 Fifteen RCTs (n = 48,656) and 7 non-RCTs (n = 62,294) met criteria for further analysis.

▪ The meta-analysis of RCTs demonstrated strong efficacy of PPSV against IPD with no statistical heterogeneity (Table 4). The evidence supporting PPSV against nonbacteremic pneumonia was largely inconclusive due to substantial statistical heterogeneity. Pneumococcal polysaccharide vaccine had little effect on all-cause mortality.

▪ The meta-analysis of non-RCTs also demonstrated efficacy in protecting against IPD.

Although effective in inducing a protective immune response in immunocompetent adults, PPSV generally does not induce a robust immune response in infants and toddlers as these populations respond poorly to T-cell–independent antigens, such as pure polysaccharide antigens.9

Pneumococcal Conjugate Vaccine

The PCV contains polysaccharide antigens covalently linked to protein, which induces a T-cell–dependent response that is more effective for use in young children. The introduction of the 7-valent PCV (PCV7) for children in 2000 provided protection against the 7 serotypes responsible for most invasive pneumococcal infections. This was followed by a dramatic decrease in the incidence of IPD in both adults and children.10 Although the incidence of infections caused by serotypes covered by the vaccine decreased dramatically, there has been a modest increase in the incidence of infections caused by non-vaccine serotypes, particularly for serotype 19A (Table 5).

Immunization and Serotype Replacement

Serotype replacement, as in the case of serotype 19A, is a likely consequence of the widespread use of the pneumococcal vaccine. Serotype 19A presents additional challenges given that these strains often exhibit multidrug resistance to commonly used antibacterials, including amoxicillin, the macrolides, and certain cephalosporins.11 PPSV23 and the recently approved PCV13 both provide protection against this serotype. However, continued surveillance will be necessary to identify whether there will be other emerging pneumococcal serotypes with the growing use of PCV13.

PNEUMOCOCCAL IMMUNIZATION: GUIDELINES AND RECOMMENDATIONS

Current Advisory Committee on Immunization Practices Guidelines for Adult Vaccination

Guidelines for adult vaccination reflect many of the risk factors associated with IPD—age, presence of chronic illness, current smoker, and children in daycare (<6 years old).6 In 2010, CDC’s Advisory Committee on Immunization Practices (ACIP) updated the adult pneumococcal immunization guidelines for PPSV23 to include 2 key at-risk populations—those with asthma and cigarette smokers.12

Pneumococcal Revaccination

According to current guidelines, most adults will receive a single dose of PPSV23. However, revaccination of some adults after immunization with PPSV23 is recommended to ensure optimal protection against IPD. Vaccines containing polysaccharide antigens are effective in inducing an antibody response but are limited in developing long-term immune memory.13 Elderly patients in particular have been found to experience reduced concentrations of pneumococcal antibodies compared with younger adults after vaccination.14

The ACIP guidelines recommend that all persons 65 years or older should be vaccinated once.12 Those who received the vaccine before age 65 for any indication should receive a second dose of the vaccine at 65 years or later if at least 5 years have passed since their previous dose. Revaccination is also recommended once 5 years after the first dose for persons 19 to 64 years with functional or anatomic asplenia and for persons with immunocompromising conditions.

Revaccination of adults with PPSV has been associated with a slightly higher risk of injection-site reactions.15 These self-limited local injection-site reactions typically occur within 2 days of vaccination and resolve in a median of 3 days after vaccination. However, this risk does not represent a contraindication for revaccination for recommended groups. In general, the frequency of adverse events after revaccination was similar compared with rates after the initial vaccination (Table 6). Several reports have raised the possibility of hyporesponsiveness with revaccination of PPSV23.13,16,17 However, the results are of uncertain clinical relevance and should not impact the decision to revaccinate when indicated.

Immunizing the Immunocompromised: HIV-Infected Persons

The incidence of IPD in adults with AIDS has decreased by 25% since the introduction of the PCV7 for children; however, the rate remains substantially higher compared with non–HIV-infected adults.4 Analysis of the strains responsible for IPD in adults with AIDS had revealed that some serotype replacement has occurred after the introduction of PCV7 in children—in 2006 to 2007, the percentage of IPD cases caused by non-vaccine serotypes were 92% for serotypes not included in PCV7, 61% for serotypes not included in PCV13, and 45% for serotypes not included in PPSV23.4

The antibody response may be diminished in HIV-infected persons, particularly in individuals with low CD4 counts. The use of highly active antiretroviral therapy may improve response. A systematic review of the literature provides moderate support for the use of PPSV23 in HIV-infected adults.18

Current recommendations support the use of PPSV23 as a safe and potentially effective preventive measure for HIV-infected adults.19 When vaccinating HIV-infected persons, an optimal immune response occurs when CD4 counts are more than 200 cells/μL, although the vaccine may be offered to those with lower CD4 counts. Many HIV-infected adults also have other risk factors for pneumococcal infection, and so vaccination in these persons can be critical.

Revaccination for HIV-infected adults can also be important for sustaining protective antibody levels. ACIP guidelines recommend revaccination in immunocompromised adults after 5 years of the initial dose. In HIV-infected individuals, revaccination every 5 years can be considered.19 It may also be useful to consider revaccination in those individuals who were initially vaccinated with a CD4 count less than 200 cells/μL but who later present with CD4 more than 200 cells/μL while on highly active antiretroviral therapy.19

Immunizing the Immunocompromised: Transplant Recipients

Transplant recipients are at higher risk of infection, which subsequently places them at greater risk of morbidity and mortality compared with immunocompetent adults. Among solid organ transplant recipients, the antibody responses after vaccination are lower and decrease faster compared with nontransplant recipients.20 It is recommended to administer the vaccine before transplantation for optimal response followed by revaccination after 5 years.

One study evaluated the antibody response of 43 kidney transplant recipients after vaccination with PPSV23.21 Four weeks after vaccination, patients showed a significant increase in total antibody concentration against the 14 serotypes analyzed (P<0.0001), and there was a significant increase in the number of serotypes recognized (P<0.0001). Higher renal function was associated with a better antibody response in these patients.

Hematopoietic stem cell transplant recipients are faced with immune suppression due to hematopoietic ablative therapy before transplantation, immunosuppressive treatments to combat graft-versus-host disease, and often underlying disease. Because of this, antibody titers against vaccine-preventable diseases decrease 1 to 4 years after transplantation if patients are not revaccinated.22 Current recommendations for vaccinating hematopoietic stem cell transplant recipients suggest initiating a vaccination regimen 3 to 6 months after transplantation with 3 doses of PCV followed by a dose of PPSV23.23

Among transplant recipients, there is limited evidence suggesting an advantage in eliciting an immune response from either the conjugate or the polysaccharide vaccines. One randomized clinical trial assessed the value of a prime-boost strategy in solid organ transplant recipients.24 Adult patients were randomized to receive either (1) PCV7 followed by PPSV23 booster 8 weeks later (primed group) or (2) placebo followed by PPSV23. After 16 weeks, response to at least 1 serotype was observed in 85.7% of the primed group and 91.2% of the unprimed group (P value not significant). Differences in functional antibody titers and the number of serotypes to have responded were also not significant between the 2 treatment groups, suggesting that the prime-boost strategy did not enhance immunogenicity in this patient population.

Nonetheless, current immunization rates fall well short of the 90% immunization goal set by the Department of Health and Human Services Healthy People 2010 Initiative.26 The Healthy People 2020 program aims to reduce the incidence of new IPD among older adults by 25%. A significant improvement in immunization rates will certainly help to achieve this goal.

IMPROVING ADULT IMMUNIZATION RATES

A broad range of healthcare providers can play a critical role in improving vaccination rates by increasing awareness of the disease, the vaccine, and the personal risk a patient takes by not being vaccinated. They must be prepared to acknowledge and address fears and misconceptions a patient may have about the vaccine. They must also take a proactive approach in screening their patients for vaccine eligibility and advocating for vaccination when indicated. In addition, healthcare providers should review and update patient immunization records and promote immunization at each visit.

Standing orders can be an effective tool to increase the efficiency of administering the pneumococcal vaccine to eligible adults.27 Standing orders empower all eligible healthcare providers within a practice to initiate the order and administer the vaccine. When designing and using standing orders, all eligible healthcare providers, including nurses, pharmacists, and others, should be included to the extent allowed by state laws to maximize vaccination opportunities.

All healthcare providers, particularly in the primary care setting, should proactively recommend vaccination, even if the patient declines the initial request. Primary care professionals should also promote the utilization of community pharmacists by recommending their services to eligible patients who are considering vaccination.

CONCLUSIONS

In summary, pneumococcal disease is responsible for significant morbidity and mortality, much of which is preventable by use of the available vaccines. However, despite the accessibility of effective vaccines, immunization of eligible adults is underused. Clinicians must take a proactive role in recommending the vaccine to eligible adults and should encourage strategies to remove barriers to immunization utilization.